Mechanisms of reduced digitalis tolerance with advancing age in the guinea pig

In the present study, arrhythmogenic toxicity of cardiac glycoside ouabain was investigated in guinea pigs after intravenous infusion (5 micrograms/kg/min). Guinea pigs of 18-24 months of age required significantly (P less than 0.05) lower doses of ouabain that 3-month-old animals (72 +/- 3 vs 100 +/- 3 micrograms/kg) for the initiation of cardiac arrhythmias. Investigation of Na(+)-Ca2+ exchange in the isolated sarcolemmal vesicles revealed a marked reduction in the Na(+)-dependent Ca2+ uptake. Kinetic analysis of these data has demonstrated a 70% reduction in Vmax and reduced affinity for Ca2+ in vesicles from 18-month-old as compared to 3-month-old guinea pigs. The rate of Na(+)-dependent Ca2+ efflux was also markedly lower in the vesicles of older animals, and the vesicles retained more Ca2+ after 3 min of Na(+)-dependent Ca2+ extrusion than did those from 3-month-old animals. The results suggest that the sensitivity to cardiac glycocide increases with age and may be associated with altered sarcolemmal Na(+)-Ca2+ exchange activity.